Drug Discovery Platform PDD

Barcelona, Spain

Drug Discovery Platform PDD

Barcelona, Spain
SEARCH FILTERS
Time filter
Source Type

Blasi D.,Drug Discovery Platform PDD | Pinto M.,University Pompeu Fabra | Nieto J.,Ramon Llull University | Arsequell G.,CSIC - Institute of Advanced Chemistry of Catalonia | And 4 more authors.
Amyloid | Year: 2011

We have previously designed and synthesized ligands that stabilize the transthyretin (TTR) tetramer, in order to obtain therapeutically active compounds for familial amyloid polyneuropathy. We are hereby reporting a drug design strategy to optimize these ligands to target familial amyloid cardiomyopathy, through the following steps: (a) Structure Activity Relationship (SAR) analyses of the ligands described previously for the TTR tetramer, classified in structurally similar families; (b) drug design/optimization of TTR ligands through docking in the TTR tetramer three-dimensional structure and through optimization of physicochemical/pharmacokinetic/selectivity properties; (c) comparative structural analyses of selected amyloidogenic and non-amyloidogenic TTR mutants and native TTR structures; and (d) virtual screening of commercially available ligands and therapeutically active compounds (repurposing) towards wild-type and mutant TTR tetramer structures. First results in steps (a) and (d) of this strategy will be reported.© 2011 Informa UK, Ltd.


Pinto M.,Research Unit on Biomedical Informatics GRIB | Blasi D.,Drug Discovery Platform PDD | Nieto J.,Ramon Llull University | Arsequell G.,CSIC - Institute of Advanced Chemistry of Catalonia | And 4 more authors.
Amyloid | Year: 2011

A computational analysis was performed on a selected group of 13 TTR-ligand crystallographic complexes in order to deduce information useful for drug design and discovery. The results obtained can be summarized as follows: (1) the binding site of TTR is a large and very flexible cavity, which is composed of three regions with different chemical features; (2) ligands bind to TTR in forward or reverse modes depending on the conformation adopted by the serine and threonine residues located at the end of the cavity; (3) no relationship could be found between the binding mode of the ligands and their TTR fibrillogenesis inhibitory activity; (4) regardless of the structure, chemical properties or binding mode of the ligand to TTR, there is always a contribution of residues Lys15, Leu17, Ala108, Leu110, Ser117 and Thr119 to ligand binding and finally, (5) the most active compounds are characterised by the presence of at least one halogen atom in the HBP1/HBP1' or HBP3/HBP3' pockets.© 2011 Informa UK, Ltd.

Loading Drug Discovery Platform PDD collaborators
Loading Drug Discovery Platform PDD collaborators